Effectiveness of Exercise, Cognitive Behavioral Therapy, and Pharmacotherapy on Improving Sleep in Adults with Chronic Insomnia: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials

Despite the well-established treatment effectiveness of exercise, cognitive behavioral therapy for insomnia (CBT-I), and pharmacotherapy on improving sleep, there have been no studies to compare their long-term effectiveness, which is of clinical importance for sustainable management of chronic insomnia. This study compared the long-term effectiveness of these three interventions on improving sleep in adults with chronic insomnia. MEDLINE, PsycINFO, Embase, and SPORTDiscus were searched for eligible reports. Trials that investigated the long-term effectiveness of these three interventions on improving sleep were included. The post-intervention follow-up of the trial had to be ≥6 months to be eligible. The primary outcome was the long-term effectiveness of the three interventions on improving sleep. Treatment effectiveness was the secondary outcome. A random-effects network meta-analysis was carried out using a frequentist approach. Thirteen trials were included in the study. After an average post-intervention follow-up period of 10.3 months, both exercise (SMD, −0.29; 95% CI, −0.57 to −0.01) and CBT-I (−0.48; −0.68 to −0.28) showed superior long-term effectiveness on improving sleep compared with control. Temazepam was the only included pharmacotherapy, which demonstrated superior treatment effectiveness (−0.80; −1.25 to −0.36) but not long-term effectiveness (0.19; −0.32 to 0.69) compared with control. The findings support the use of both exercise and CBT-I for long-term management of chronic insomnia, while temazepam may be used for short-term treatment.


Introduction
Chronic insomnia is the most common sleep disorder in the general population [1], with a worldwide prevalence rate ranging from 3.9% to 22.1% depending on the diagnostic criteria used [2][3][4][5]. Insomnia increases the risk of developing various physical and mental disorders, including cardiovascular diseases, depression, and cognitive impairment [6]. Insomnia is also associated with increased health-care utilization and high economic and societal burdens [7,8]. Currently, cognitive-behavioral therapy for insomnia (CBT-I)

Study Selection 2.2.1. Type of Studies
We included randomized controlled trials investigating both the treatment effectiveness and long-term effectiveness of exercise, CBT-I, and pharmacotherapy on improving sleep in adults with chronic insomnia. As the intervention duration might vary in different settings and we wanted to examine the treatment effectiveness of the three approaches from a wide range of clinical practices, there were no restrictions on the intervention duration of the study, which is the time duration between the baseline measurement and the post-intervention measurement. To assess the long-term effectiveness, the post-intervention follow-up period of the study, which is the time duration between the post-intervention measurement and the last follow-up measurement, had to be ≥ 6 months to be eligible.

Types of Participants
The study participants were adults with chronic insomnia aged ≥18 years. Chronic insomnia was defined as having difficulty in initiating sleep, maintaining sleep, or with early morning awakening, with complaints of impaired daytime functioning and the sleep difficulty occurring at least three nights per week and lasting for at least three months, which is in accordance with standard diagnostic criteria, such as the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and the International Classification of Sleep Disorders, Third Edition [32][33][34]. Studies involving insomnia patients with common comorbidities such as depression, anxiety, and fibromyalgia were also included to enhance the generalizability of the findings. However, studies that involved participants with comorbid conditions that would prevent them from joining the exercise intervention, such as severe musculoskeletal disorders or dementia, were excluded to avoid violation of the transitivity assumption [35].

Types of Interventions
Exercise was defined as "planned, structured, and repetitive bodily movement aimed to improve and/or maintain one or more components of physical fitness" according to the American College of Sports Medicine guidelines [36]. CBT-I was defined as a multimodal approach incorporating at least two of following components: cognitive therapy, stimulus control, sleep restriction, sleep hygiene, and relaxation therapy [10,24]. To stringently compare the treatment effectiveness and long-term effectiveness of exercise to that of CBT-I, we excluded studies with online or self-help CBT-I interventions, which are commonly recognized as effective but not fully comparable as traditional face-to-face CBT-I interventions [37,38]. Studies with online or unsupervised exercise interventions were subsequently excluded to avoid violation of the transitivity assumption [35]. Lastly, pharmacotherapy was defined as a pharmacological intervention using any of the eight sleep-promoting agents (suvorexant, eszopiclone, zaleplon, zolpidem, triazolam, temazepam, ramelteon and doxepin) recommended by the American Academy of Sleep Medicine (AASM) clinical practice guidelines [9].

Outcome Measures
The primary outcome of this study was the long-term effectiveness of the three interventions on improving sleep, which reflected the sleep-promoting effects of the interventions during the post-intervention follow-up period and was operationalized as the score of the validated scale used to subjectively measure sleep improvement at the last post-intervention follow-up measurement. The secondary outcome was the treatment effectiveness of the interventions on improving sleep, which reflected the sleep-promoting effects of the interventions during the intervention period and was operationalized as the score of the validated scale used to subjectively measure sleep improvement at the post-intervention measurement. When multiple validated scales were used in the study, a reductive meta-analytic approach was applied to randomly select one of the scales for data synthesis and to yield a representative effect for the network meta-analysis [39,40].

Data Extraction and Quality Assessment
Two independent researchers extracted the samples sizes, scores, and standard deviations of the subjective sleep assessment scales in each trial. Any disagreements on the extracted data were resolved by consensus. We also extracted information on participant characteristics (e.g., age, sex, and comorbidity) and trial characteristics (e.g., first author, type of intervention and control, intervention and follow-up duration) using Covidence, a web-based systematic review tool [41].

Risk of Bias and Confidence Assessment
Risk of bias was rated using the Cochrane risk of bias assessment tool (RoB-2), which comprehensively assessed five components: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome (measurement appropriateness and blindness), and selection of the reported results [42]. Confidence of the accumulated evidence in the network was assessed by the Confidence in Network Meta-Analysis (CINeMA), a web application of the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) ratings approach [43,44]. Additional information on RoB-2 and CINeMA are provided in S2 of the Supplementary Materials.

Data Synthesis and Analysis
We conducted a network meta-analysis with a frequentist framework using the netmeta package in the statistical software R (version 4.1.2). The network included: (1) exercise, (2) CBT-I, (3) pharmacotherapy, and (4) control. We used a random-effects pairwise metaanalysis to estimate standardized mean differences (SMD) for direct comparisons. Indirect evidence was assessed using the network. The random effects netmeta model was used to control for multi-arm randomized controlled trials. Results of the primary outcome (long-term effectiveness) and secondary outcome (treatment effectiveness) were expressed as SMDs with 95% confidence intervals. The pairwise between-study heterogeneity was examined using Cochran's Q statistics. In addition, T 2 was calculated to determine the level of variance between studies, and I 2 was used to determine the percentage of variance due to between-study heterogeneity.

Transitivity Assessment
The transitivity assumption was tested by assessing the distribution of patients and intervention characteristics across the comparisons [35]. The statistical manifestation of transitivity-consistency among the comparisons was also measured to assess the agreement of direct and indirect evidence in the network [35]. Local and global approaches were applied to measure consistency using netsplit and decomp.design functions, respectively. We presumed that every participant in the included studies could potentially be randomized to any of the treatments compared.

Sensitivity Analysis
Three sensitivity analyses were performed to test the robustness of the results. First, we extended the minimal follow-up length from 6 months to 12 months by including studies with a follow-up period ≥12 months to examine the longer-term effectiveness of the three interventions. Second, we excluded studies with high level of indirectness. Last, we included all the data generated by every scale in the included studies. Given the small number of studies in each comparison group, subgroup and meta-regression analyses could not be performed to further explore potential sources of heterogeneity.

Role of the Funding Source
This study was supported by General Research Fund of Research Grants Council (RGC), Hong Kong University Grants Committee (project number: 17112819) and Seed Fund for Basic Research of the University of Hong Kong. The funding bodies had no role in the study design, data collection, analysis and interpretation, report writing, or the decision to submit for publication.

Overview of Studies
The literature search identified 9447 potential studies. After excluding duplicate studies, 6674 studies were screened by title and abstract, and 6449 studies were excluded. In total, 225 full-text articles were retrieved for in-depth screening. In total, 212 studies were excluded due to a post-intervention follow-up period <6 months (n = 136), ineligible study design such as crossover study (n = 42), secondary analysis (n = 21), ineligible population (n = 9) and ineligible outcome (n = 4). A total of 13 studies were included in the main analysis ( Figure  This study was supported by General Research Fund of Research Grants Council (RGC), Hong Kong University Grants Committee (project number: 17112819) and Seed Fund for Basic Research of the University of Hong Kong. The funding bodies had no role in the study design, data collection, analysis and interpretation, report writing, or the decision to submit for publication.

Overview of Studies
The literature search identified 9447 potential studies. After excluding duplicate studies, 6674 studies were screened by title and abstract, and 6449 studies were excluded. In total, 225 full-text articles were retrieved for in-depth screening. In total, 212 studies were excluded due to a post-intervention follow-up period <6 months (n = 136), ineligible study design such as crossover study (n = 42), secondary analysis (n = 21), ineligible population (n = 9) and ineligible outcome (n = 4). A total of 13 studies were included in the main analysis ( Figure S1    Exercise interventions included tai chi exercise [22,23,45] and aerobic and musclestrengthening exercise [23]. All CBT-I interventions included at least cognitive therapy, stimulus control, and sleep restriction [22,[45][46][47][48][49][50][51][52][53][54][55]. All pharmacotherapy interventions prescribed temazepam [53,55]. The control interventions included sleep education, sleep hygiene, relaxation training, usual care, and placebo. The intervention durations ranged between 5 and 16 weeks and the post-intervention follow-up durations ranged between 6 and 24 months. The outcome measurements included Athens insomnia scale (AIS) [56], insomnia severity index (ISI) [57], insomnia symptom questionnaire (ISQ) [58], Pittsburgh sleep quality index (PSQI) [59], and sleep diary (sleep efficiency) [60]. AIS, ISI, and ISQ measured the perceived insomnia severity. PSQI and the sleep efficiency domain of the sleep diary reflected the subjective sleep quality. These five instruments are commonly used in research and clinical settings to subjectively assess the sleep improvement after treatments.

Risk of Bias and Confidence
One study was assessed to have a low risk of bias and 12 studies had some concerns, whereas no study was assessed to have a high risk of bias (Table S2 of

Transitivity
The plausibility of the transitivity assumption was examined by assessing the eligibility criteria, the patient characteristics, and the study designs. The major patient characteristics and intervention characteristics did not significantly differ among studies (Table 1, and  Table S1 of the Supplementary Materials). Overall, the assumption of transitivity was valid, and we presumed that every participant in the included studies could potentially be allocated to any of the compared interventions.

Sensitivity Analysis
Sensitivity analyses confirmed the robustness of the results. Both exercise and CBT-I showed sustained sleep-promoting effects in all three sensitivity analyses (Table S5 of

Discussion
This is the first network meta-analysis to comparatively evaluate the treatment effectiveness and long-term effectiveness of exercise, CBT-I, and pharmacotherapy on improving sleep in adults with chronic insomnia. Our results demonstrated that both exercise and CBT-I showed superior long-term effectiveness on improving sleep compared to the control, while pharmacotherapy (temazepam) showed excellent treatment effectiveness. Exercise demonstrated significant sleep-promoting effects, with a small-to-medium effect size compared to the control (SMD, −0.29) after an average 10.3-month post-intervention follow-up [61]. Takemura et al. reported that the sleep-promoting effects of aerobic exercise remained significant (SMD, −0.37; 95% CI, −0.55 to −0.18) for 3 to 6 months post-intervention in cancer patients with poor sleep quality [62], whereas our meta-analysis demonstrated that the sleep-promoting effects of exercise can last much longer. In the CINeMA confidence assessment, the selection of a clinically significant effect size of −0.4 was based on a previous meta-analysis [30], in which CBT-I was shown to elicit long-term improvements on sleep after ≥6-month post-intervention follow-up when compared to the control [30]. In the current meta-analysis, although the long-term effectiveness of exercise did not reach the pre-defined clinically significant effect size of −0.4, exercise was found to elicit a greater hypnotic effect (SMD, −0.32) when the minimal follow-up period was extended from 6 months to 12 months (average follow-up length increased from 10.3 to 16.8 months). More importantly, there were no significant differences between the long-term effectiveness of exercise and that of CBT-I. Considering the limited accessibility and scalability of CBT-I in the community, our study supports the use of exercise as an alternative non-pharmacological treatment for the long-term management of chronic insomnia in adults [25]. At the end of the interventions, all three treatments were effective in improving sleep compared to the control. Pharmacotherapy (temazepam) showed the greatest magnitude of improvement (SMD, −0.80), followed by CBT-I (SMD, −0.60) and exercise (SMD, −0.44). We appraised the magnitudes of improvement with previous literature to assess whether the results are representative of the existing exercise, CBT-I and pharmacotherapy trials. Milne et al. included 6 exercise interventional studies in a meta-analysis and found that exercise significantly improved sleep (SMD, −0.47; 95% CI, −0.86 to −0.08) [16]. One previous meta-analysis by Koffel et al. summarized the treatment effectiveness of CBT-I (SMD, −0.85; 95% CI, −0.57 to −1.14) from 8 trials [63]. Pharmacotherapy was also found to be able to significantly improve sleep after the intervention (SMD, −0.87; 95% CI, unreported) in a meta-analysis with 21 studies included [16]. Indeed, the magnitudes of improvements found in our study are in line with the previous meta-analyses [11,16,63], suggesting that although only 13 trials were included in our study, these studies are still representative of the existing literature. More importantly, using a network meta-analytical approach, this is the first study demonstrated that exercise had comparable treatment effectiveness to that of CBT-I (SMD, 0.16; 95% CI, −0.07 to 0.40). Our findings support current physical activity guidelines recommending regular exercise in adults to improve sleep [17,18].

Limitations
This meta-analysis had several limitations that should be noted. First, only two pharmacotherapy studies were included and both studies prescribed temazepam as the intervention [53,55], which limited the generalizability of our findings. The current results showing that temazepam did not demonstrated significant long-term effectiveness on improving sleep must be interpreted with caution and cannot be generalized to other pharmacotherapies, such as suvorexant, eszopiclone, zaleplon, zolpidem, triazolam, ramelteon and doxepin. During the full-text screening of eligible studies, we found that a considerable number of high-quality studies reported the superior treatment effectiveness of different pharmacotherapy interventions over placebo [64][65][66][67][68][69][70], and several meta-analytical studies have also proved the therapeutic effects of sleep medications [11,71,72]. However, it is regrettable to point it out that most of the pharmacotherapy intervention studies did not set a post-intervention follow-up, or only designed with a relatively short post-intervention follow-up ranging from 24 h to 3 months, which largely limited the current investigation of the long-term effectiveness of pharmacotherapy on improving sleep. In line with previous review articles by Morin et al. [25] and Perlis et al. [73], our study further added evidence showing that the sleep-promoting effects of pharmacotherapy, specifically temazepam, were not sustainable after ≥ 6 months post-intervention follow-up, and highlighting the urgent need for future studies to delineate the long-term effectiveness of pharmacotherapy interventions.
Another limitation of this study is that besides one study investigated the sleeppromoting effects of aerobic exercise and resistance training [23], the exercise interventions in the other two included studies were both Tai Chi-based [22,45], which might prevent our current conclusion to be extended to different exercise modalities. Nevertheless, one recent network meta-analysis summarized the comparative treatment effectiveness of different exercise modalities on improving sleep quality in older adults, and the results showed that Tai Chi had similar sleep-promoting effects as 7 other different exercise regimens, including yoga, Pilates, walking, muscle endurance training, muscle endurance training combined with walking, resistance training and resistance training combined with walking [21]. We believe that the long-term sleep-promoting effects of Tai Chi will also be comparable to those of other exercise modalities. One of our previous works demonstrated that the aerobic and muscle-strengthening exercise exerted similar long-term beneficial effects to Tai Chi on improving sleep [23]. Future studies are warranted to investigate the comparative long-term effectiveness of different exercise modalities.
The third limitation is that only subjective sleep measurements were included in the study, which might inherit the risk of self-report bias. Nevertheless, it should be noted that the diagnosis of chronic insomnia heavily relies on subjective sleep assessments [32]. The AASM clinical guidelines for the evaluation and management of chronic insomnia in adults suggests that subjective sleep assessments aid baseline evaluation and outcome follow-up in patients with chronic insomnia [1]. Evaluating the long-term effectiveness and treatment effectiveness of exercise, CBT-I, and pharmacotherapy on improving sleep using subjective sleep measurements is valid and in accordance with clinical practice.

Conclusions
This network meta-analysis showed that both exercise and CBT-I were effective in improving sleep in adults with chronic insomnia in the long term (≥ 6-month post-intervention follow up), while the long-term effectiveness of temazepam was not superior to that of the control. All three interventions demonstrated excellent treatment effectiveness. These findings support the use of both exercise and CBT-I for long-term management of adults with chronic insomnia, and that temazepam may be used for short-term insomnia treatment.
Informed Consent Statement: Not applicable. Data Availability Statement: Data collected in this study are available upon request.

Conflicts of Interest:
The authors declare no conflict of interest.